2122 - Phase I Study of CC-90011 in Patients With Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma (R/R NHL)

Background

CC-90011 is a selective, reversible inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-tumor activity against neuroendocrine cells in vitro and in xenograft models.

Methods

This is a phase I, first-in-human clinical study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/week in 28-day cycles. Primary objectives were to determine safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD).

Results

As of 15 Jan 2018, 35 pts were enrolled; 34 with advanced solid tumors, including 17 with neuroendocrine tumors (NETs) and 1 with R/R NHL. They received escalating doses of CC-90011 at 1.25 mg (n = 4), 2.5 mg (n = 5), 5 mg (n = 6), 10 mg (n = 4), 20 mg (n = 4), 40 mg (n = 6), or 80 mg (n = 4). The MTD and RP2D have not yet been established. The median age was 61 y (range, 22-75), 19 (54%) were male, with 2 (range, 1-4) median number of prior systemic anticancer therapies. No dose-limiting toxicities were reported. The only treatment-related grade 3/4 adverse event (AE) was thrombocytopenia (9%). Serious AEs occurred in 24% of pts; none were treatment-related. Peak plasma concentrations were 2-4 hours post-dose and terminal elimination half-life was approximately 64 hours; increase in plasma exposures was dose proportional. Blood biomarker analyses showed increasing suppression of MMD and MYL9 expression with higher CC-90011 doses suggesting target engagement at doses ≥ 40 mg. Overall, 13 (39%) pts had stable disease (SD). Prolonged SD (≥4 mo) was observed in 5 pts with solid tumors; notably, 3 of those pts had bronchial NETs [5 mg (n = 1), 20 mg (n = 1) and 40 mg (n = 1)]. Preliminary PD results from NETs showed CC-90011 decreased chromogranin A levels, correlating with clinical benefit.

Conclusions

CC-90011 has dose-proportional PK with target engagement at tolerable doses with preliminary evidence of antitumor activity in advanced solid tumors and R/R NHL, including prolonged SD particularly in pts with NETs.

Clinical trial identification

NCT02875223.

Legal entity responsible for the study

Celgene Corporation.

Funding

Celgene Corporation.

Editorial Acknowledgement

Editorial assistance was provided by BioConnections, LLC.

Disclosure

A. Hollebecque: Honoraria: Merck Serono; Consulting or advisory role: Gritstone Oncology; Travel, accommodations: Amgen. J. de Bono: Consulting or advisory role: AstraZeneca, GlaxoSmithKline, Genentech, Pfizer, Merck, Sharp & Dhome, Bayer, Merck Serone, Janssen, Astellas, Seattle Genetics; Research funding: AstraZeneca, Sanofi, Genentech, GlaxoSmithKline, Daiichi, Taiho, Merck Serone, Merck Sharp & Dhome, Sierra; Speaker's bureau: AstraZeneca. R. Plummer: Honoraria: Novartis, Bristol-Myers Squibb, AstraZeneca; Consulting or advisory role: Clovis Oncology, Bayer, Novartis, Pierre Faber, Karus Therapeutics, Genmab, Octimet; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents, royalties, other intellectual property: Clovis Oncology; Travel, accommodations: Merck Sharpe & Dhome, Bristol-Myers Squibb. S. Mora, A. Harding, Z. Nikolova: Employment, equity ownership, travel, accommodations: Celgene, Inc. A. Nguyen: Employment, equity ownership, patents, royalties, other intellectual property: Celgene Corporation. E. Filvaroff: Employment: Celgene; Equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents, royalties, other intellectual property: Celgene, Genentech. M. Lamba: Employment, equity ownership, research funding: Pfizer Inc., Celgene Corporation; Patents, royalties, other intellectual property: Pfizer, Inc. K. Liu, M. Zuraek: Employment, equity ownership: Celgene Corporation. J. DiMartino: Employment, leadership, equity ownership: Celgene Corporation. All other authors have declared no conflicts of interest.